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Inhibition of Matrix Metalloproteinase-9 by a Barbiturate-Nitrate Hybrid Ameliorates Dextran Sulphate Sodium-Induced Colitis: Effect on Inflammation-Related Genes.

Research paper by Shane S O'Sullivan, Jun J Wang, Maria T MT Pigott, Neil N Docherty, Noreen N Boyle, Samuel Kana SK Lis, John F JF Gilmer, Carlos C Medina

Indexed on: 13 Jan '17Published on: 13 Jan '17Published in: British Journal of Pharmacology



Abstract

Matrix metalloproteinase-9 is upregulated in Ulcerative Colitis and implicated in the pathology of the disease. In this study, we have examined the effects of a barbiturate-based MMP inhibitor incorporating a nitric oxide donor/mimetic group (dinitrate-barbiturate) in the intestinal injury induced by dextran sulphate sodium (DSS).In-vivo experiments were carried out using male Wistar rats given DSS 5% ad libitum in drinking water. The dinitrate-barbiturate, non-nitrate equivalent, nitrate side chains alone or vehicle were administered rectally, twice daily. Matrix metalloproteinase-9 release was measured by gelatin zymography and analysis of gene expression was carried out using RT-qPCR. Taq-Man low density arrays were used to evaluate the expression of 91 inflammatory genes in the rat colon.The dinitrate-barbiturate inhibited the induction and activity of MMP-9 during DSS colitis in the rat. This occurred in association with significant reductions in the colitic response to DSS as assessed by an established clinical disease activity index and a pathological colitis grade score. The compound modified expression rates of numerous inflammation-related genes in the colon.This study proves the efficacy of the dinitrate-barbiturate in DSS-induced colitis. Therefore, barbiturate-nitrate hybrids may emerge as a promising anti-inflammatory approach in inflammatory bowel disease. This article is protected by copyright. All rights reserved.